There is a compelling need to develop therapeutic approaches specifically designed to reduce neurological deficits after stroke. Human umbilical cord blood cells (HUCBCs) treatment dose-dependently improves functional outcome after stroke. UCBCs are associated with a lower risk of graft-versus-host disease (GVHD), and UCBCs are younger than adult bone marrow stem cells and therefore potentially more vigorous. Our preliminary data show that the combination of sub-therapeutic doses of simvastatin with HUCBCs increases exogenously administered cell migration into the ischemic brain, and additively improves the cell-based therapeutic outcome after stroke. Thus, altering the ischemic tissue with agents to promote a cell receptive microenvironment may amplify the therapeutic modality of cell-based therapy. We propose that cell-based therapy can be enhanced by making the tissue more receptive to the administered cells by creating a microenvironment within the ischemic cerebral tissue that facilitates cell-based induction of brain plasticity. In this proposal, we seek to investigate the effect of combination of simvastatin and HUCBCs to amplify the therapeutic effect of HUCBC cell-based therapy, to improve the functional outcome after stroke. We will test the effects of combination cell-based and pharmacological therapies in a clinically relevant model of embolic stroke in rat. In Aim 1, we hypothesize that the combination treatment of stroke with HUCBCs and simvastatin promotes additive or super-additive improvement of neurological functional outcome in adult rats. In Aim 2, we investigate whether combination treatment with HUCBCs and simvastatin increases HUCBC migration into the ischemic brain. We hypothesize, that combination treatment with HUCBCs and simvastatin increases stromal derived factor 1 (SDF1) expression and enhances HUCBC homing/migration and survival in the ischemic brain. The increased HUCBC number in the ischemic brain increases functional outcome after stroke. Combination treatment with HUCBCs and simvastatin reduces infarct volume, and enhances angiogenesis and neurogenesis in the ischemic brain in rats. We will elucidate the effect of combination HUCBCs and simvastatin therapy with the intention of developing a viable restorative therapy to translate to the stroke population. Our study is a prototype and a proof of principle designed to augment the therapeutic response to the administration of exogenous cells for the treatment of stroke. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of morbidity and long-term disability. Treatment of stroke has taken essentially two approaches, cellular and pharmacological therapy. We propose to combine cell and pharmacological treatment, to enhance recovery of neurological function post stroke. Our preliminary data show that the human umbilical cord blood cells (HUCBCs) treatment of stroke improves functional outcome. Combination of sub- therapeutic doses of simvastatin with HUCBCs increases exogenously administered cell migration into the ischemic brain and additively improves the therapeutic outcome after stroke. Thus, we propose that HUCBC cell-based therapy can be enhanced by making the tissue more receptive to the administered cells by creating a microenvironment within the ischemic cerebral tissue that facilitates cell-based induction of brain plasticity. A clinically relevant embolic middle cerebral artery occlusion (MCAo) rat model will be used in this study, which will provide new and important data regarding novel therapeutic targets for stroke recovery.